Antigen Presenting Cell Defects in Autoimmune Diabetes

描述(申请人提供)：在人类和NOD小鼠中，1型糖尿病(T1D)是多重易感基因(IDD)之间相互作用的结果，这些基因诱导T细胞介导的自身免疫破坏产生胰岛素的胰岛β细胞。我们发现在NOD小鼠中，Idd基因在H2 g7 MHC单倍型内外的相互作用会导致造血源抗原提呈细胞(APC)的缺陷，这有助于糖尿病T细胞的生成和激活。我们的总体目标是确定导致NOD小鼠糖尿病APC功能障碍的基因的身份和功能。APC亚群包括B淋巴细胞、巨噬细胞和树突状细胞(DC)。这些APC亚群有助于NOD小鼠在不同水平的T细胞发育和激活的T1D发育。NOD巨噬细胞和DC不能正常成熟，这似乎是该菌株在胸腺或外周发育过程中删除或灭活自身反应性T细胞的能力受损的原因之一。我们的数据表明，NOD小鼠DC分化受损反过来与自然杀伤T(NKT)细胞缺陷有关，自然杀伤T(NKT)细胞也是这种菌株的特征。超激动剂α-半乳糖神经酰胺对NKT细胞的激活抑制NOD小鼠T1D的发育，我们的数据表明这是DC下游成熟的结果，DC聚集在胰腺淋巴结(PLN)中，通过未知的机制阻断致病T细胞反应。我们的第一个特定目标是确定NKT细胞激活覆盖NOD小鼠DC成熟缺陷的机制，以及这如何随后抑制T1D。由于其独特的能力，通过特定的质膜结合免疫球蛋白(Ig)分子摄取β细胞抗原，B淋巴细胞是APC亚型，最有效地激活NOD小鼠的糖尿病原性CD4T细胞反应。我们发现NOD小鼠的特征是在正常情况下删除或丧失表达自身反应性Ig分子的B淋巴细胞的过程中存在缺陷，但目前尚不清楚这是否代表Idd基因控制的功能障碍。因此，目标2是定位导致NOD小鼠B淋巴细胞耐受诱导缺陷的基因，以便最终确定它们的身份。我们的第三个目标是从机制上确定NOD小鼠B淋巴细胞耐受诱导缺陷的相关基因。尽管有胰岛素治疗，但T1D的并发症仍然经常会产生致命的影响。我们提议的研究的成功完成可能最终为预防这种毁灭性疾病的发展提供手段。

DESCRIPTION (provided by applicant): In both humans and NOD mice type 1 diabetes (T1D) results from interactions between multiple susceptibility (Idd) genes that elicit T cell mediated autoimmune destruction of insulin producing pancreatic beta cells. We have found that in NOD mice interactions between Idd genes both within and outside the H2g7 MHC haplotype engender defects in hematopoietically derived antigen presenting cells (APC) which contribute to the generation and activation of diabetogenic T cells. Our overall goal is to determine the identity and function of genes contributing to diabetogenic APC dysfunctions in NOD mice. APC subsets include B-lymphocytes, macrophages, and dendritic cells (DC). These APC subsets contribute to T1D development in NOD mice at different levels of T cell development and activation. NOD macrophages and DC do not mature normally which appears to contribute to this strain's impaired ability to delete or inactivate autoreactive T cells either during their development in the thymus or in the periphery. Our data indicate impaired DC differentiation in NOD mice is in turn linked to defects in natural killer T (NKT) cells that also characterize this strain. NKT cell activation with the superagonist alpha-galactosylceramide inhibits T1D development in NOD mice, and our data suggests this results from the downstream maturation of DC which accumulate in the pancreatic lymph nodes (PLN) where they block pathogenic T cell responses through unknown mechanisms. Our first specific aim is to determine the mechanisms by which NKT cell activation overrides DC maturation defects in NOD mice, and how this subsequently inhibits T1D. Due to their unique ability to take up beta cell antigens through specific plasma membrane bound immunoglobulin (Ig) molecules, B-lymphocytes serve as the APC subtype which most efficiently activates diabetogenic CD4 T cell responses in NOD mice. We have found NOD mice are characterized by defects in processes that normally delete or anergize B-lymphocytes expressing autoreactive Ig molecules, but it remains unknown if this represents an Idd gene controlled dysfunction. Hence, aim 2 is to map the genes contributing to B-lymphocyte tolerance induction defects in NOD mice in order to ultimately determine their identity. Our third aim is to then mechanistically characterize the genes contributing to B-lymphocyte tolerance induction defects in NOD mice. Despite the availability of insulin treatment, the complications of T1D can still too often have lethal effects. Successful completion of our proposed studies might ultimately provide means for preventing the development of this devastating disease.